基于基因组的特征分析表明，在海洋来源的曲霉属真菌中， Stephacidin 和 Notoamide 抗癌剂的装配过程中存在两步异戊烯基化步骤。
Genome-based characterization of two prenylation steps in the assembly of the stephacidin and notoamide anticancer agents in a marine-derived Aspergillus sp.
机构信息
Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
出版信息
J Am Chem Soc. 2010 Sep 15;132(36):12733-40. doi: 10.1021/ja1049302.
Abstract
Stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing a core bicyclo[2.2.2]diazaoctane ring system. These bioactive fungal secondary metabolites have a range of unusual structural and stereochemical features but their biosynthesis has remained uncharacterized. Herein, we report the first biosynthetic gene cluster for this class of fungal alkaloids based on whole genome sequencing of a marine-derived Aspergillus sp. Two central pathway enzymes catalyzing both normal and reverse prenyltransfer reactions were characterized in detail. Our results establish the early steps for creation of the prenylated indole alkaloid structure and suggest a scheme for the biosynthesis of stephacidin and notoamide metabolites. The work provides the first genetic and biochemical insights for understanding the structural diversity of this important family of fungal alkaloids.
摘要
Stephacidin 和 notoamide 天然产物属于一类含有核心双环[2.2.2]二氮杂辛烷环系统的prenylated indole 生物碱。这些具有生物活性的真菌次生代谢产物具有一系列不寻常的结构和立体化学特征，但它们的生物合成仍未被阐明。本文基于海洋来源的 Aspergillus sp 的全基因组测序，报道了该类真菌生物碱的第一个生物合成基因簇。详细表征了催化正常和反向prenyltransferase 反应的两个中心途径酶。我们的结果确定了prenylated indole 生物碱结构形成的早期步骤，并提出了 stephacidin 和 notoamide 代谢物生物合成的方案。这项工作为理解这一重要的真菌生物碱家族的结构多样性提供了第一个遗传和生化见解。
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2
STUDIES ON THE BIOSYNTHESIS OF THE STEPHACIDINS AND NOTOAMIDES. TOTAL SYNTHESIS OF NOTOAMIDE S.斯蒂芬酰胺类和诺托酰胺类的生物合成研究。诺托酰胺S的全合成。
Heterocycles. 2010 Dec 31;82(1):461-472. doi: 10.3987/COM-10-S(E)19.
3
Solanapyrone synthase, a possible Diels-Alderase and iterative type I polyketide synthase encoded in a biosynthetic gene cluster from Alternaria solani.茄呢醇合酶，一种可能的 Diels-Alderase 和迭代型 I 聚酮合酶，编码于来自茄病镰刀菌的生物合成基因簇中。
Chembiochem. 2010 Jun 14;11(9):1245-52. doi: 10.1002/cbic.201000173.
4
The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria.二甲基烯丙基色氨酸合酶的结构揭示了真菌和细菌中芳香族异戊烯基转移酶的共同结构。
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14309-14. doi: 10.1073/pnas.0904897106. Epub 2009 Aug 12.
5
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Nat Prod Rep. 2009 Aug;26(8):977-86. doi: 10.1039/b713024b. Epub 2009 May 22.
6
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Appl Microbiol Biotechnol. 2009 Sep;84(4):631-9. doi: 10.1007/s00253-009-2128-z. Epub 2009 Jul 25.
7
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Curr Med Chem. 2009;16(2):218-31. doi: 10.2174/092986709787002772.
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J Nat Prod. 2009 Jan;72(1):44-52. doi: 10.1021/np800501m.
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